S100A9

The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in the inhibition of casein kinase and altered expression of this protein is associated with the disease cystic fibrosis. This antimicrobial protein exhibits antifungal and antibacterial activity. [provided by RefSeq, Nov 2014]

S100 Calcium Binding Protein A9

S100A9 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response (PubMed:12626582, PubMed:15331440, PubMed:20103766, PubMed:8423249, PubMed:16258195, PubMed:19122197, PubMed:21325622).
It can induce neutrophil chemotaxis, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism (PubMed:12626582, PubMed:15331440, PubMed:20103766).
Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions (PubMed:8423249, PubMed:16258195, PubMed:19122197).
The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase (PubMed:15331440, PubMed:21325622).
Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX (PubMed:15642721, PubMed:22808130).
The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities (PubMed:8423249, PubMed:19534726).
Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration (PubMed:15598812, PubMed:21487906).
Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER) (PubMed:19402754).
Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade (PubMed:19402754, PubMed:22804476).
Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn2+ which is essential for microbial growth (PubMed:19087201).
Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3 (PubMed:19935772).
Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK (PubMed:22363402).
Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants (PubMed:22489132, PubMed:21912088).
Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread (PubMed:16258195).
Has transnitrosylase activity; in oxidatively-modified low-densitity lipoprotein (LDL(ox))-induced S-nitrosylation of GAPDH on 'Cys-247' proposed to transfer the NO moiety from NOS2/iNOS to GAPDH via its own S-nitrosylated Cys-3 (PubMed:25417112).
The iNOS-S100A8/A9 transnitrosylase complex is proposed to also direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif (PubMed:25417112).

Biological Process activation of cysteine-type endopeptidase activity involved in apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process antimicrobial humoral immune response mediated by antimicrobial peptideManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process apoptotic processIEA:UniProtKB-KW
Biological Process astrocyte developmentManual Assertion Based On ExperimentIBA:GO_Central
Biological Process autocrine signalingManual Assertion Based On ExperimentIBA:GO_Central
Biological Process autophagyManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process cell-cell signalingManual Assertion Based On ExperimentTAS:ProtInc
Biological Process chronic inflammatory responseManual Assertion Based On ExperimentIBA:GO_Central
Biological Process defense response to bacteriumManual Assertion Based On ExperimentTAS:UniProtKB
Biological Process defense response to fungusManual Assertion Based On ExperimentTAS:UniProtKB
Biological Process inflammatory responseManual Assertion Based On ExperimentTAS:ProtInc
Biological Process innate immune responseIEA:UniProtKB-KW
Biological Process leukocyte migration involved in inflammatory responseManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process modulation of process of another organismManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process neutrophil aggregationManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process neutrophil chemotaxisManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process peptidyl-cysteine S-nitrosylationManual Assertion Based On ExperimentIBA:GO_Central
Biological Process peptidyl-cysteine S-trans-nitrosylationManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of cell growthManual Assertion Based On ExperimentTAS:UniProtKB
Biological Process positive regulation of inflammatory responseManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of intrinsic apoptotic signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of neuron projection developmentISS:ARUK-UCL
Biological Process positive regulation of NF-kappaB transcription factor activityManual Assertion Based On ExperimentTAS:UniProtKB
Biological Process regulation of cytoskeleton organizationManual Assertion Based On ExperimentTAS:UniProtKB
Biological Process regulation of integrin biosynthetic processManual Assertion Based On ExperimentIBA:GO_Central
Biological Process response to lipopolysaccharideManual Assertion Based On ExperimentIBA:GO_Central
Biological Process sequestering of zinc ionManual Assertion Based On ExperimentTAS:UniProtKB

Secreted
Cytoplasm
Cytoplasm, cytoskeleton
Cell membrane
Predominantly localized in the cytoplasm. Upon elevation of the intracellular calcium level, translocated from the cytoplasm to the cytoskeleton and the cell membrane (PubMed:18786929).
Upon neutrophil activation or endothelial adhesion of monocytes, is secreted via a microtubule-mediated, alternative pathway (PubMed:15598812).

Phosphorylated. Phosphorylation inhibits activation of tubulin polymerization.
S-nitrosylation of Cys-3 is implicated in LDL(ox)-induced S-nitrosylation of GAPDH at 'Cys-247' through a transnitrosylase mechanism involving a iNOS-S100A8/9 complex (PubMed:25417112).
Methylation at His-105 by METTL9 reduces zinc-binding without affecting heterodimerization with S100A8.